On the other hand, Yang et al. 134  reported a series of peptide inhibitors with a greater inhibitory potency. In general, they systematically changed the backbone of inhibitor 29. As a result, they were able to identify more specific residues for each subsite (compounds 36–38; Figure 12): At first, the P1‐lactam ring was identified as a more specific moiety for the S1‐site, forming multiple hydrogen‐bond interactions with the enzyme as can be seen in the crystal structure (36); P2‐leucine showed a fourfold increased inhibitory activity when compared to the P2‐phenylalanine or ‐4‐fluorophenylalanine (37). A lipophilic tert‐butyl residue was recognized to be a better P3‐moiety than the P3‐valine (38). Finally, the replacement of P4‐methylisoxazole with a benzyloxy group was the best option for activity enhancement (compare 29 vs 36). They all showed moderate to high antiviral activity against HCoV‐229E in cell‐based assays.